Canadian Task Force on Preventive Health Care

1998 Update Note

Administration of Pneumococcal Vaccine
 

Prepared by Elaine E.L. Wang, MD, CM, FRCPC, Department of Pediatrics, University of Toronto

 

 


 

Contents


 

Since the last update on pneumococcal vaccination in 1991 , a number of developments have taken place which may potentially impact on decisions regarding vaccine. The first is the appearance of resistance amongst Streptococcuspneumoniae (pneumococci) to penicillin. The other is the publication of a meta-analysis of all randomized controlled trials of pneumococcal vaccination .
 

Epidemiology of Streptococcus pneumoniae

    1. pneumoniae is the commonest single cause of community acquired infections including bacterial pneumonia, bacteremia, and otitis media . The organism has remained exquisitely susceptible to penicillin until the 1990’s despite the first report of clinical resistance in 1967 in Papua, New Guinea . High rates (44% to 70%) of resistance have been reported from Spain , South Africa , Hungary, and Korea and moderately high rates (24 to 29%) in Hong Kong , Japan , the United States , and Bulgaria . In the United States, reports in the latter part of the 1980’s suggested resistance rates of pneumococci to penicillin of the order of 30% . Until recently, rates of resistance in Canada were consistently under 3% . However, surveys conducted in the 1990’s have observed rates of 7% and 12% with higher rates in the more recent studies .
Unlike the resistance seen with Haemophilus influenzae and Moraxella catarrhalis, which is due to elaboration of beta lactamase, an enzyme which breaks down beta lactam antibiotics such as penicillins and cephalosporins, resistance among S. pneumoniae develops through alterations in penicillin binding proteins . Because there are 6 different penicillin binding proteins, increasing resistance occurs as chromosomal changes alter the structures of each of these proteins . Pneumococci may be divided into susceptible strains, with a minimal inhibitory concentration (MIC) < 0.1 m g/ml and non-susceptible strains with MIC ³ 0.1 m g/ml . The subgroup among the non-susceptible strains with MIC ³ 2 m g/ml are considered resistant . Furthermore, because cephalosporins also bind to penicillin binding proteins, alterations in specific proteins also confer cephalosporin resistance. Equally concerning, however, is the much higher predilection for penicillin non susceptible pneumococci vs. penicillin susceptible pneumococci to also exhibit resistance to other classes of antibiotics. This resistance is not dependent on penicillin binding proteins and has been described with quinolones, macrolides, tetracyclines, chloramphenicol, and trimethoprim-sulfa . Thus, pneumococci that are penicillin non-susceptible also show less susceptibility to most antibiotic alternatives as well.

The relevance of reduced pneumococcal susceptibility depends on the site of infection . Because of the high achievable levels of penicillins in blood and lung fluid, outcome in patients with bacteremia and pneumonia due to penicillin non-susceptible organisms does not appear to be worsened . Similarly, because of the benign outcome of acute otitis media, amoxicillin remains the first line antibiotic for this indication . On the other hand, because of the much lower achievable drug levels in the cerebrospinal fluid relative to the MIC of the pneumococcus and because of reports of failures with empiric therapy with third generation cephalosporins, vancomycin is added to the regimen for treatment of possible pneumococcal meningitis.

Risk factors for infection with resistant organisms include recent hospitalization, recent receipt of antibiotics, and day care attendance . Recent receipt of antibiotics increases nasopharyngeal colonization from 9 to 21% to 39 to 67% and invasive disease from 4 to 39% to 30 to 77% . The confluence of these three factors in young children may explain the high frequency of infection in children in particular .

In summary, the increase in antibiotic resistance rates amongst pneumococci appears to be increasing in Canada. This has led to changes in empiric therapy of meningitis in children. Because serotypes in the vaccine include resistant strains, use of vaccine is an attractive option to reduce the morbidity due to infection by these strains. However, currently available vaccine is not conjugated and does not stimulate an adequate response in children under two years of age, who are at greatest risk of pneumococcal meningitis. Hopes for conjugate pneumococcal vaccine to mimic the success of conjugate Haemophilus influenzae type b vaccine has spurred clinical trials of such a vaccine in children .

Vaccine Efficacy

Fine and colleagues completed a meta-analysis of all randomized clinical trials of pneumococcal vaccine . A MEDLINE search from 1966 to 1991, manual review of article references, communications with pneumococcal vaccine investigators and vaccine manufacturers identified nine randomized controlled trials. Studies involving children and those in which the vaccine contained four valences (or serogroups) or less were excluded in this meta-analysis. Summary odds ratios and risk differences were calculated for outcomes, but the latter is because heterogeneity across studies was observed. Several subgroup analyses were planned, in particular, population risk of pneumococcal vaccine (high vs. low risk). The high risk population includes those aged greater than 55 years of age, those with predefined underlying chronic medical conditions, constituting that group for which vaccination is currently recommended .

Significant risk differences were observed in two pneumococcal infection-related outcomes: definitive pneumococcal pneumonia where the risk difference was 4/1000 and definitive pneumococcal pneumonia with vaccine types only of 8/1000. In other words, 250 subjects need to be vaccinated to prevent one case definitive pneumococcal pneumonia. The differences in other outcomes including mortality, all cause pneumonia and bronchitis were not significant and not necessarily suggesting efficacy of vaccination. The subgroup analysis for population risk observed the benefit from vaccination to be accrued in low risk, but not high risk populations. Quality analyses of the studies involving high risk populations had actually observed these to be of higher quality and this lack of benefit cannot be attributed to poor study quality. Sensitivity analyses stressed that exclusion of several studies materially affected risk differences for pneumococcal related study outcomes.

In summary, this excellent meta-analysis suggests efficacy of unconjugated pneumococcal vaccine in preventing definitive pneumococcal pneumonia. The number that need to be vaccinated to accrue such a benefit is arguably quite large. More importantly, the benefit appears to be predominantly in otherwise healthy subjects rather than the high risk adults for whom pneumococcal vaccination is currently recommended.

Recommendations

Review of new literature that appeared since the last update on pneumococcal vaccine does not justify any change in recommendation at this time. The meta-analysis specifically excluded studies other than randomized controlled studies, which were the major evidence in support of pneumococcal vaccination. These studies were available at the time of the original Task Force recommendations. The lack of efficacy amongst the high risk group may be related to the inability of at least some members of this heterogeneous group to mount an adequate immune response to vaccine .

The efficacy of vaccination should be revisited with availability of results from randomized trials of conjugate pneumococcal vaccine. Such a vaccine may overcome the problems of poor immunogenicity in the subgroup of adults for whom a number of groups recommend vaccination. Until that time, there appears no urgency in offering pneumococcal vaccination to the population at high risk from pneumococcal disease.

References

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Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials. Arch Intern Med. 1994;154:2666-2677.

Butler JC, Hofmann J, Cetron MS, et al. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: An update from the Centers for Disease Control and Prevention's Pneumococcal sentinel surveillance system. J Infect Dis. 1996;174:986-993.

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Fenoll A, Bourgon CM, Munoz R, Vicioso D, Casal J. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 1979-1989. Rev Infect Dis. 1991;13:56-60.

Friedland IR, Klugman KP. Antibiotic-resistant pneumococcal disease in South African children. Am J Dis Child. 1992;146:920-923.

Marton A. Pneumococcal antimicrobial resistance: the problem in Hungary. Clin Infect Dis. 1992;15:106-111.

Lee HJ, Park JY, Jang SH, Kim JH, Kim EC, Choi KW. High incidence of resistance to multiple antimicrobials in clinical isolates of Streptococcus pneumoniae from a university hospital in Korea. Clin Infect Dis. 1995;20:826-835.

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Dixon JMS, Lipinski AE, Graham MEP. Detection and prevalence of pneumococci with increased resistance to penicillin. Can Med Assoc J. 1977;117:1159-1161.

Jette LP, Lamothe F, and The Pneumococcal Study Group. Surveillance of invasive Streptococcus pneumoniae infection in Quebec, Canada,from 1984 - 86: serotype distribution, antimicrobial susceptibility, and clinical characteristics. J Clin Microbiol. 1989;27:1-5.

Simor AE, Rachlis A, Louie L, Goodfellow J, Louie M. Emergence of penicillin-resistant Streptococcus pneumoniae in southern Ontario, 1993-94. Can J Infect Dis. 1995;6:157-160.

Simor AE, Louie M, The Canadian Bacterial Surveillance Network, Low DE. Canadian national survey of prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae. Antimicrob Ag Chemother. 1996;40:2190-2193.

McDougal LK, Rasheed JK, Biddle JW, Tenover FC. Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae in the United States. Antimicrob Ag Chemother. 1995;39:2282-2288.

The National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. . Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards; 1997.

Matsumura S, De Azavedo J, Fletcher A, et al. An in vitro study of new and old antimicrobials in the treatment of penicillin-resistant Streptococcus pneumoniae. . ICAAC. San Francisco; 1995:88.

Committee of Infectious Diseases American Academy of Pediatrics. Therapy for children with invasive pneumococcal infections. Pediatrics. 1997;99:289-298.

Plouffe JF, Breiman RF, Facklam RR. Bacteremia with Streptococcus pneumoniae. Implications for therapy and prevention. JAMA. 1996;275:194-198.

Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med. 1995;333:474-480.

Bradley JS, Kaplan SL, Klugman KP, Leggiardo RJ. Consensus: Management of infections in children caused by Streptococcus pneumoniae with decreased susceptibility to penicillin. Pediatr Infect Dis J. 1995;14:1037-1041.

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Kellner JD, Ford-Jones EL, Matlow A, et al. K 17. Nasopharyngeal (NP) carriage of Streptococcus pneumoniae (SP) in children in Daycare Centres (DCC). . 36th ICAAC. New Orleans: ASM; 1996:252.

Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med. 1995;333:481-486.

Vadheim CM, Greenberg DP, Eriksen E, et al. Protection provided by Haemophilus influenzae type b conjugate vaccines in Los Angeles: A case-control study. Pediatr Infect Dis J. 1994;13:274-280.

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Dagan R, Melamed R, Muallem M, et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect Dis. 1996;174:1271-1278.

Dagan R, Melamed R, Zamir O, Leroy O. Safety and immunogenicity of tetravalent pneumococcal vaccines containing 6B, 14, 19F, and 23F polysaccharides conjugated to either tetanus toxoid or diptheria toxoid in young infants and their boosterability by native polysaccharide antigens. Pediatr Infect Dis J. 1997;16:1053-1059.

American College of Physicians Task Force on Adult Immunization. Guide for Adult Immunization. . 2nd ed. Philadelphia: American College of Physicians; 1990.

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